tbuckley/cabot-search huggingface dataset:
Abstract 14368: Growth Differentiation Factor-15 in Heart Failure Across Body Mass Index Categories: The PREHOSP-CHF Study
Authors: Moritake Iguchi, Hiromichi Wada, Tsuyoshi Shinozaki, masahiro suzuki, Yoichi Ajiro, Morihiro Matsuda, Akihiro Koike, Tomomi Koizumi, masatoshi shimizu, Yujiro Ono, Takashi Takenaka, Satoru Sakagami, Yukiko Morita, Kazuteru Fujimoto, Kazuya Yonezawa, Kazuro Yoshida, Akiyo Ninomiya, Toshihiro Nakamura, JUNICHI FUNADA, Yutaka Kajikawa, Yoishifumi Oishi, Toru Kato, Kazuhiko Kotani, Mitsuru Abe, Masaharu Akao, Koji Hasegawa
Journal: Circulation (2022)

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9&lt;, ≤23.4), and high (&gt;23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.
Abstract 13012: Atrial Fibrillation Symptom Improvement Following De Novo Catheter Ablation: Trajectories and Predictors of Symptom Resolution
Authors: Meghan Reading Turchioe, Alexander Volodarskiy, Winston Guo, Brittany Taylor, Mollie Hobensack, Jyotishman Pathak, David J Slotwiner
Journal: Circulation (2022)

Introduction: Atrial fibrillation (AF) symptom relief is a primary indication for catheter ablation, but the impact of ablation on AF symptoms is not well characterized. The objective of this study was to describe AF symptom documentation in electronic health records (EHRs) pre- and post-ablation and identify correlates of post-ablation symptoms. Methods: We evaluated EHRs of AF patients (n=1293) in a large, urban health system from 2010-2020 who underwent ablation and had at least one encounter note within 30 days of the ablation. We extracted structured data about patient demographics, medications, diagnoses, and encounters, and symptom data from unstructured clinical notes using natural language processing. We used Cochran’s Q tests with post-hoc McNemar’s tests to determine whether the prevalence of symptoms differed significantly pre- and 3, 6, 9, and 12 months post-ablation. We used bivariate logistic regression models to estimate the unadjusted odds of symptom prevalence by personal or clinical characteristics at 6 and 12 months post-ablation. Results: Compared to pre-ablation, the prevalence of any AF symptom decreased but anxiety and weakness increased post-ablation (Table 1). The unadjusted odds of any symptoms 12 months post-ablation were associated with Black/African-American (odds ratio [OR]=0.35; 95% confidence interval [CI]=0.14-0.92) or another race (OR=0.39, 95% CI=0.16-0.95) versus Asian race, Hispanic/Latino ethnicity (OR=2.40, 95% CI=1.28-4.39) versus non-Hispanic/Latino, antiarrhythmic medication (OR=0.62, 95% CI=0.46-0.80) versus no medication, smoking history (OR=0.70, 95% CI=0.53-0.94) versus no history, and heart failure (OR=0.73, 95% CI=0.55-0.97) versus no heart failure. Conclusion: Symptom patterns post-ablation are heterogeneous. Findings warrant confirmation with larger, more representative datasets, which may be informative for patients whose primary goal for undergoing an ablation is symptom relief.
Abstract 13579: <i>TAX1BP3</i> -Encoding TAX1-Binding Protein 3 is a Novel Genetic Cause of Autosomal Recessive Arrhythmogenic Cardiomyopathy and Causes Pro-Arrhythmic Ryanodine Receptor 2-Mediated Calcium Leak
Authors: Robin M Perelli, Heidi Cope, Alexander S Behura, Anna Q Ponek, Mary Moya-Mendez, Bo Sun, Leonie Kurzlechner, Jordan E Ezekian, Qixin Yang, Michael J Campbell, Zebulon Z Spector, Catherine Rehder, David B Goldstein, Paul C Tang, Vandana Shashi, Andrew P Landstrom
Journal: Circulation (2022)

Introduction: Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease where fibrofatty tissue replaces healthy myocardium. AC predisposes to ventricular arrhythmias and sudden cardiac death. We identified biallelic variants in the TAX1BP3- encoded tax1-binding protein 3 (TAX1BP3) in a genetically elusive family with AC. TAX1BP3 has putative roles in canonical Wnt signaling, but its function in the heart is unknown. Our goal is to identify novel mechanisms of AC development to develop therapeutics to mitigate or reverse disease progression. Hypothesis: We hypothesize that genetic loss of TAX1BP3 suppresses normal canonical Wnt-signaling in the heart, allowing pathologic remodeling and arrhythmogenesis associated with AC development. Methods: Whole exome sequencing of an AC genotype-negative family was performed. Induced pluripotent stem cells generated from peripheral blood mononuclear cells (PBMCs) from were differentiated into cardiac myocytes (iPSC-CMs) for 3 kindred. Line scans using CAL-520-labeled calcium were conducted with a Zeiss confocal microscope to capture calcium sparks after pacing iPSC-CMs. Sarcoplasmic reticulum store was measured after adding 10mM caffeine to iPSC-CMs. Adipogenesis in iPSC-CMs was visualized by immunofluorescence with Nile Red stain. Results: TAX1BP3 M78T/del variant co-segregates with AC in an autosomal recessive inheritance mode in an AC genotype-negative family. TAX1BP3 M78T/del PBMCs had reduced proliferation and qPCR from whole blood identified decreased canonical Wnt signaling. iPSC-CMs M78T/del have decreased intracellular calcium store, increased adipogenesis, and increased calcium leak associated with spontaneous calcium release events. Small molecule Wnt-activator BML-284 normalized calcium leak in iPSC-CMs M78T/del . Conclusions: Our results demonstrate that loss-of-function of TAX1BP3 is pro-arrhythmic and driven by calcium leak in iPSC-CMs which can be rescued by Wnt activation. We identified a new AC-associated gene, TAX1BP3, that has not been studied in the heart. Further studies are needed to explore the impact of TAX1BP3 on cardiac Wnt signaling, but our findings implicate Wnt activation as a possible treatment for AC - currently an untreatable, deadly disease.
Abstract 14324: Improving Rates of Uncontrolled Atrial Fibrillation Through Obstructive Sleep Apnea Screening and Management: Preliminary Data From the OFIB Institutional Quality Initiative
Authors: Ravi Thakker, Peter Rasmussen, Elizabeth Davis, Steven Mai, Mahnoor Javed, Deaa Abu Jazar, Salman Salehin, Chandani Patel, Ivana Garza, Khaled Chatila, Wissam Khalife, Hani Jneid, Lindsay Sonstein
Journal: Circulation (2022)

Introduction: Untreated obstructive sleep apnea (OSA) is a major cause of uncontrolled atrial fibrillation (AF). It represents a high prevalence and incidence, as well as significant cause of mortality. Uncontrolled AF with recurrent emergency department (ED) visits and inpatient admissions poses a burden to patient quality of life and increased risk of cardiovascular events, in addition to healthcare costs. Hypothesis: We aim to reduce ED visits and hospitalizations for General Internal Medicine resident clinic patients with OSA and uncontrolled AF over the next year by 10%. Methods: We identified approximately 382 patients with inclusion criteria of age 18-70 years with a history of both AF and OSA without documented CPAP use. Interventions included a week long educational session to all residents starting March 2022, standardizing CPAP device ordering/monitoring, and patient education. A protocol for sleep study ordering and CPAP titration was implemented across clinics. The next phase is inpatient screening and referrals. Results: Prior to our intervention date, 14.7% of our study population presented with uncontrolled AF in the past year. Since our interventions, 2.4% have presented with uncontrolled AF. Conclusions: Our preliminary interventions have shown a numerical trend towards decreasing rates of uncontrolled AF in patients with OSA at our institution. Our interventions are ongoing with periodic evaluation of outcomes. Our findings support the need for a comprehensive approach targeting both providers and patients.
Abstract 12884: Reduction of Alpha-1,4-Galactosyltransferase (A4GALT) by Antisense Oligonucleotide Mitigates Globotriaosylsphingosine (lyso-gb3) Accumulation in Fabry Mice
Authors: Xin Yi Yeap, Asa Wahlander, Ting-yuan T Yeh, Adam E Mullick
Journal: Circulation (2022)

Fabry disease is one of the most common lysosomal storage disorders that results from a deficiency of the enzyme alpha galactosidase A (GLA). The deficiency leads to systemic accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, Lyso-Gb3, in multiple organs, which can progress into end stage renal disease, heart failure or stroke in Fabry patients. Despite current FDA-approved enzyme replacement and chaperone therapies, unmet medical needs remain. A4GALT is the key enzyme that catalyzes the incorporation of galactose to lactosylceramide to form Gb3. We tested the hypothesis whether a substrate reduction approach utilizing an antisense oligonucleotide (ASO) targeting A4GALT can ameliorate Lyso-Gb3 accumulation in a mouse model of Fabry disease, the α-Gal A knockout (GLA KO). Potent and well tolerated mouse A4GALT ASO leads were identified in wildtype (WT) mice and evaluated in a dose response (5, 20, 40, 80 mg/kg/week) in GLA KO mice. A4GALT reductions of up to 90% were observed in the kidney. Lyso-Gb3 level was determined by LC-MS and was found to be reduced in a dose-dependent manner by up to 75% and 65% in plasma and kidney, respectively. In conclusion, A4GALT ASO treatment in GLA KO mice results in dose-dependent reductions of plasma and kidney lyso-Gb3, a key endpoints of disease efficacy that are monitored in the clinic. Hence, a substrate reduction therapy by inhibiting A4GALT with ASO could be a promising approach for treatment of Fabry disease.
Abstract 13462: Valve-in-Valve Transcatheter Mitral Valve Replacement versus Redo Surgical Mitral Valve Replacement for Degenerated Bioprosthetic Valves: A Systematic Review and Meta-Analysis
Authors: Mahmoud Ismayl, Muhannad Abbasi, Mostafa Zaalouk, Ahmed S Aboeata, Nandan S Anavekar, Andrew M Goldsweig
Journal: Circulation (2022)

Introduction: Valve-in-valve transcatheter mitral valve replacement (ViV-TMVR) and redo surgical mitral valve replacement (redo-SMVR) are two treatment strategies for patients with bioprosthetic mitral valve dysfunction. We conducted a systematic review and meta-analysis to compare the outcomes of ViV-TMVR versus redo-SMVR. Methods: We searched PubMed, EMBASE, Cochrane, and Google Scholar for studies comparing outcomes of ViV-TMVR versus redo-SMVR in degenerated bioprosthetic mitral valves. We used a random effects model to calculate risk ratios (RRs) with 95% confidence intervals (CIs). Outcomes included in-hospital, 30-day, 1-year, and 2-year mortality, stroke, bleeding and vascular complications, acute kidney injury (AKI), arrhythmias, and hospital length of stay (LOS). Results: Six observational studies with a total of 1,339 subjects were included. Median follow-up was 2 years. Compared to redo-SMVR, ViV-TMVR was associated with significantly lower in-hospital (RR 0.42; 95% CI 0.25-0.70; p=0.001) and 30-day mortality (RR 0.49; 95% CI 0.24-0.98; p=0.04) but similar 1-year (RR 0.97; 95% CI 0.64-1.47; p=0.89) and 2-year mortality (RR 1.14; 95% CI 0.71-1.81; p=0.59). Stroke, bleeding, AKI, and arrhythmias were less frequent and hospital LOS was shorter with ViV-TMVR, however vascular complications were similar between both strategies. Conclusion: In patients with degenerated bioprosthetic mitral valves, ViV-TMVR is associated with better outcomes compared to redo-SMVR including lower in-hospital and 30-day mortality, lower complication rates, and shorter hospital LOS. Given these findings and the ongoing advances in transcatheter therapeutics, ViV-TMVR may be preferred over redo-SMVR, particularly in individuals at intermediate-to-high surgical risk.
Abstract 12876: Post-Transcriptional Regulation of Cardiac Fatty Acid Metabolism by the Tandem Zinc Finger Mrna Binding Protein Tristetraprolin
Authors: Mohammad Keykhaei, Hsiang-Chun Chang, Tatsuya Sato, Konrad Sawicki, Jason S. Shapiro, Yuki Tatekoshi, Hossein Ardehali
Journal: Circulation (2022)

Introduction: Heart failure (HF) is characterized by a switch from predominantly fatty acid (FA) to glucose metabolism, but the molecular pathways involved in this switch are not totally understood. Identification of novel pathways regulating cellular metabolism could facilitate the development of new therapies. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich elements (AREs) in the 3’ untranslated region (UTR) of mRNA molecules and causes their degradation. Its expression is regulated by mTOR, a key protein involved in cellular metabolism. Our preliminary data suggested a link between TTP and FA metabolism in the heart. Thus, we hypothesized that TTP regulates cardiac FA metabolism and that its deletion prevents the development of HF by increasing FA uptake and metabolism in the heart. Results: TTP downregulation in cultured cardiomyocytes resulted in higher palmitate uptake and oxidation, while its overexpression had the opposite effect. Since TTP regulates its targets at the mRNA level, we studied the mRNA levels of ARE-containing genes involved in lipid metabolism, and found that only PPARα mRNA to be significantly increased with TTP downregulation. Furthermore, we demonstrated that TTP physically interacts with PPARα mRNA, and the activity of a luciferase reporter harboring full-length PPARα 3’UTR is increased with TTP downregulation. Additionally, PPARα mRNA is stabilized with TTP knockdown. We then studied the role of TTP in cardiac FA metabolism using mice with cardiac-specific (cs) TTP knockout (KO). Consistent with our in vitro data, cs-TTP KO mice displayed higher fatty acid utilization compared to littermate controls but maintained normal cardiac function at baseline. We also demonstrated a significantly higher TTP levels in failing human and mouse cardiac samples, suggesting that TTP levels are altered in HF. Conclusion: Our results demonstrate that TTP is a novel regulator of cardiac FA metabolism through its effect on PPARα, and that its levels are increased in HF. Thus, modulation of TTP may be a viable therapeutic approach for HF.
Abstract 14838: Prevalence and Outcomes of Prosthetic Valve Endocarditis Post-Tavr: A Proportion Meta-Analysis
Authors: Jeffy Susan Varghese, Mounika Reddy Vadiyala, Song Peng Ang, Jia Ee Chia, Akhil Reddy, Angela Ishak, Sadia Yaqoob
Journal: Circulation (2022)

Introduction: Prosthetic valve endocarditis (PVE) may occur after trans-catheter aortic valve replacement (TAVR), resulting in bio-prosthetic valve dysfunction. We aim to assess the clinical characteristics and long-term outcomes post TAVR. Methods: We performed a systematic literature search in PubMed, Scopus, and Embase for relevant articles from inception until June 01, 2022. Primary outcome was all-cause mortality. Secondary outcomes include acute kidney injury, stroke, systemic embolisation, heart failure and valve re-intervention. All endpoints were pooled using a random-effect model. Results: A total of 33 studies were included, comprising 346,094 patients who underwent TAVR. Amongst the various co-morbidities, most common were diabetes (11%), chronic kidney disease (8%) and chronic obstructive pulmonary disease (COPD) (8%).The pooled incidence of PVE was 1% [95% CI (1%-2%)]. The most common approach was trans-femoral (n=15) (88% [95% CI (79%-95%)]) followed by trans-apical (n=9) (14% [95% CI(10%-18%)]). The most common organisms isolated were staphylococcus species (n=24) (34% [95% CI (30%-38%)]), followed by streptococcal species (n=23) in 23% and enterococcus species (n=22) in 24%. The leading complications reported were acute kidney injury (AKI) (30% [95% CI (19%-44%)]) (n=7), cerebrovascular accident (10% [95% CI (7%-14%)]) (n=13), embolisation (17% [95% CI (10%-26%)]) (n=11) and patients requiring a surgical valve replacement (12% [95% CI (8%-18%)] ) (n=14). The all-cause mortality was 49% [95% CI (41%-56%)], while the in-hospital mortality was 4% [95% CI (2%-9%)]. Conclusions: Incidence of IE post TAVR is low (1%), but is associated with a higher rate of mortality (49%) and morbidity. As a result, aggressive management is needed to reduce post-TAVR complications.
Abstract 13129: Human <i>in vitro</i> Study on Pulsed Electric Field Cardiac Ablation Cell Sensitivity
Authors: Maura Casciola, TK Feaster, Ram Anand Vadlamani, Devin Keck, Rafael V Davalos, Ksenia Blinova
Journal: Circulation (2022)

Introduction: Catheter cardiac ablation is a standard treatment for atrial fibrillation for patients that do not respond to drugs. Pulsed electric field (PEF) cardiac ablation has been proposed as a nonthermal technology to cause cell death by irreversible electroporation (IRE). IRE has shown to minimize off target damage. The lack of systematic studies to inform optimal PEF ablation parameters has significantly slowed down device development and regulatory process. Hypothesis: As part of a larger effort to develop a standard laboratory assay for PEF parameter optimization, in this study we investigate tissue specificity of IRE cardiac ablation treatments. Methods: Human induced pluripotent stem cell cardiomyocytes derived (hiPSC-CMs, Fujifilm Cellular Dynamic, Inc.), human esophageal muscle cells (HESMC, ScienCell Research Laboratories), and human bronchial epithelial cells (HBEC3-KT, ATCC) were cultured in monolayer formats on 96-well NanoFiber plates. PEF were delivered by an FID pulse generator connected to two needle electrodes (1.7 mm center-to-center distance). PEF parameters investigated in this study are: phase duration tp=1, 5, 10 μs; phase intensity Vp=284, 372, 568V; pulse repetition frequency PRF=10, 100, 1000 Hz, pulse number p#=100. We quantified IRE areas 4 hours post-treatment by propidium iodide (PI). Results: Preliminary results show that increasing the tp, Vp and decreasing the PRF resulted in a larger IRE area in all the cell types studied. For the range of PEF parameters investigated, a treatment with same tp, p# and PRF required higher Vp to induce IRE in HESMC and HBEC3-KT than hiPSC-CMs, i.e., 100 pulses with tp=5 μs and PRF=1000 Hz, to achieve the same IRE area, hiPSC-CMs needed half Vp than HESMC and HBEC3-KT. Conclusions: Our data suggests that same PEF treatments induced larger IRE areas in hiPSC-CM than in HESMC and HBEC3-KT. Future work will focus on validating these results in tissues to assess safety of IRE cardiac ablation devices.
Abstract 13499: Unravelling the Pathophysiology of Right Ventricular Maladaptive Hypertrophy in Chronic Pulmonary Hypertension Through Imaging and Omics
Authors: Ines Garcia-Lunar, Daniel Pereda, Inmaculada Jorge, Jorge Saiz Galindo, Nuria Solanes, Maria Ascaso, Carlos Galan, Juan J Rodr?guez Arias, Francisco Rafael Jiménez, Jorge Nuche Berenguer, Ana Paula V Dantas, María Morán, Emilio Camafeita, Montserrat Rigol, Coral Barbas, Jesus Vazquez, Valentin Fuster, Borja Ibanez, Ana Garcia-Alvarez
Journal: Circulation (2022)

Introduction: Right ventricular (RV) failure is the strongest determinant of survival in chronic pulmonary hypertension (PH), but its pathophysiological mechanisms remain unclear. Hypothesis: In addition to RV pressure overload, compounds liberated from the pulmonary vascular damage (identifiable by omics) may exert a detrimental effect on RV function in PH. Methods: Four different experimental models of RV pressure overload in 48 Yucatan pigs were developed: chronic postcapillary PH by pulmonary veins banding (M1); chronic PH by aorto-pulmonary shunting (M2); RV pressure overload by PA banding (thus without PH) (M3); and sham procedure (M0). Animals were evaluated at 1, 5 and 8 months after surgery by right heart catheterization, cardiac magnetic resonance (CMR), and blood/histological sampling. Unsupervised proteomic and metabolomic analyses were performed and compared among experimental groups and to the severity of RV dysfunction. Results: A total of 33 pigs completed follow-up (M1,n=8; M2,n=6; M3,n=10; and M0,n=9). As expected, M1&amp;M2-animals developed chronic PH, whereas M3-animals had severely increased RV systolic pressure without PH (Table). M3-pigs developed more severe RV hypertrophy (significantly higher mass on CMR and cardiomyocyte area on histology), but maintained normal function. In contrast, M1&amp;M2 animals developed RV systolic disfunction and increased myocardial apoptosis in M1. Plasma metabolomic and proteomic patterns differed among groups, highlighting greater inflammation and taurine/arginine deficiency in PH models (M1&amp;M2), coagulation disturbances in M1, and predominant lipidomic changes in M3. Key proteins/metabolites from coagulation, complement system and apolipoproteins pathways significantly associated with RV performance. Conclusion: Maladaptive RV hypertrophy in PH is associated with significant changes in plasma proteins and metabolites. Their identification may help to identify potential targets.